A Systematic Review on the Genetic Contribution to Tinnitus

Abstract

Purpose: To assess the available evidence to support a genetic contribution and define the role of common and rare variants in tinnitus.

Methods: After a systematic search and quality assessment, 31 records including 383,063 patients were selected (14 epidemiological studies and 17 genetic association studies). General information on the sample size, age, sex, tinnitus prevalence, severe tinnitus distribution, and sensorineural hearing loss was retrieved. Studies that did not include data on hearing assessment were excluded. Relative frequencies were used for qualitative variables to compare different studies and to obtain average values. Genetic variants and genes were listed and clustered according to their potential role in tinnitus development.

Results: The average prevalence of tinnitus estimated from population-based studies was 26.3% for any tinnitus, and 20% of patients with tinnitus reported it as an annoying symptom. One study has reported population-specific differences in the prevalence of tinnitus, the white ancestry being the population with a higher prevalence. Genome-wide association studies have identified and replicated two common variants in the Chinese population (rs2846071; rs4149577) in the intron of TNFRSF1A, associated with noise-induced tinnitus. Moreover, gene burden analyses in sequencing data from Spanish and Swede patients with severe tinnitus have identified and replicated ANK2, AKAP9, and TSC2 genes.

Conclusions: The genetic contribution to tinnitus is starting to be revealed and it shows population-specific effects in European and Asian populations. The common allelic variants associated with tinnitus that showed replication are associated with noise-induced tinnitus. Although severe tinnitus has been associated with rare variants with large effect, their role on hearing or hyperacusis has not been established.

Keywords: GWAS; Genetics; Heritability; Prevalence; Rare variation; Tinnitus.

Fig. 1

Flow diagram for study selection

Fig. 2

The genetic landscape of tinnitus. The effect of the variants associated with tinnitus as a function of their allelic frequency was observed in tinnitus genomic studies. A Blue dots represent OR for common variants associated with self-reported tinnitus in genome-wide association studies (GWAS). Odds ratios from GWAS studies were calculated from beta values from their respective studies. Some studies have not been included since information on neither beta nor odds ratio was published. B Orange dots represent OR for genes enriched in rare missense variants in exome/genome sequencing studies selecting an individual with tinnitus extreme phenotype or specific population cohorts through burden test analysis. Odds ratios represent the entire gene enrichment, not a single variant. However, the MAF value represents the MAF of the most common variant reported in the analysis. If variants were not reported, the higher MAF values were used